A program of research is proposed for studying behavioral effects of two types of drugs of major clinical, social , and theoretical important: 1) opioids, which have long represented a significant abuse problem; 2) caffeine, which is the most widely consumed behaviorally-active compound in the world, and which has many of the characteristics of a drug of abuse. The basic strategy of this research program is to use behavioral methodologies to study interactions of drugs with their neuronal substrates. The objective is to identify and characterize components of drug action that may be relevant to potential for abuse and to related phenomena, such as tolerance and physical dependence. The neuronal substrates of drug action will be characterized with receptor-selective agonists, antagonists, and tolerance and cross-tolerance. Representative compounds will be studied over a range of doses in several behavioral procedures, such as drug discrimination, food-reinforced operant responding, locomotor activity, and autotitration of reinforcement threshold for electrical brain stimulation. Experiments will be performed on rats and, often, on squirrel monkeys. This approach will help in assessing the generality of experimental findings with respect to pharmacological, behavioral, and species variables. The proposed experiments will address a number of hypotheses. Among these are: 1) Endogenous opioid peptides can modulate the behavioral effects of exogenously administered opioid drugs; 2) Similar components of drug action mediate discriminative stimulus, reinforcing stimulus, and subjective drug effects; 3) The discriminative stimulus effects of low and high doses of caffeine differ qualitatively from each other and reflect components of drug action that underlie, respectively, positive and negative mood states in humans.